Combinations of glimepiride and the thiazolidinedione for treatment of diabetes

ABSTRACT

A unit-dose pharmaceutical composition for the treatment of non-insulin dependent diabetes mellitus includes a combination of glimepiride and a thiazolidinedione insulin sensitizer, providing for the simultaneous release of each drug at rates substantially similar to those obtained with the separate administration of immediate release dosage forms of glimepiride and the thiazolidinedione. In addition, processes for the preparation of such combination unit-dose compositions and the use of such compositions for improving glycemic control are described.

FIELD OF THE INVENTION

[0001] The present invention relates to a stable unit-dose combinationfor the simultaneous delivery of glimepiride and a thiazolidinedioneinsulin sensitizer for the treatment of non-insulin dependent diabetesmellitus and improvement of glycemic control. The present invention alsorelates to processes for the preparation of such combination unit-doseformulations and the use of such combinations in the treatment ofdiabetes.

BACKGROUND OF THE INVENTION

[0002] Diabetes mellitus is a progressive metabolic disorder in humanbeings characterized by hyperglycemia and insulin resistance. It isoften associated with other disorders such as obesity, hypertension,hyperlipidemia, as well as complications such as cardiovascular disease,retinopathy, and nephropathy. Diabetes can be classified into two majorclasses: (1) Insulin dependent diabetes mellitus (IDDM or Type Idiabetes), wherein the patients lack beta cells in the pancreas, andsuch patients are treated with insulin; and (2) Non-insulin dependentdiabetes mellitus (NIDDM or Type II diabetes), wherein the patientspossess beta cells with impaired insulin secretion function.

[0003] Initially, diet and exercise is the mainstay of treatment of typeII diabetes. However, these are followed by administration of oralhypoglycemic agents. Based on their mechanism of action, theantidiabetic agents are mainly classified as follows:

[0004] 1. Biguamides, represented principally by metformin, phenforminand buformin, act by decreasing hepatic glucose production andintestinal absorption of glucose, while enhancing peripheral glucoseuptake;

[0005] 2. Sulfonylureas (also known as insulin secretagogues),represented principally by glipizide, glimepiride, glyburide,glibomuride, glisoxepide, gliclazide acetohexamide, chlorpropamide,tolazamide, and tolbutamide, among others, act by stimulating therelease of insulin from the beta cells of the pancreas;

[0006] 3. Thiazolidinediones, represented principally by the class ofglitazones including, for example, rosiglitazone, troglitazone andpioglitazone, among others, act by increasing the sensitivity of insulinreceptors in the body and diminish or eliminate the need for exogenousinsulin; and

[0007] 4. Alpha-glucosidase inhibitors, represented principally byacarbose and miglitol, among others, act by delaying absorption ofdietary carbohydrates.

[0008] As described above, these agents have a different mechanism ofaction, unique to each class of drugs. These hypoglycemic agents, inmonotherapy, are used as a first-line treatment in diabetic patients.However, after an initial positive response, these antidiabetic agentsbecome ineffective as a secondary failure sets in. Besides a qualitativeand/or quantitative deficiency of insulin secretion, the patientsdevelop insulin resistance. Sulfonylureas target one aspect ofhyperglycemia by augmenting insulin secretion from the beta cells, whilethiazolidinediones act by increasing the sensitivity of insulinavailable in the blood stream. The different yet complementarymechanisms of action suggest a therapeutically viable rationale for useof combinations of such agents in targeting hyperglycemia.

[0009] The simultaneous use of two or more biologically active agentsfrom the aforementioned different classes to achieve a synergisticeffect has previously been demonstrated. For example, three-waycombinations were described in U.S. Patent Application Publication No.20020016287 A1, which described the combination of a biguamide, aninsulin sensitizer and an insulin secretagogue for the treatment ofNIDDM. U.S. Pat. Nos. 6,166,043 and 6,172,090 claim a method forreducing the amounts and side effects of active components administeredto a diabetic patient, which comprises administering a therapeuticallyeffective amount of an insulin sensitivity enhancer in combination witha biguamide.

[0010] Sulfonylureas lower blood glucose levels acutely by stimulatingthe release of insulin from the pancreas, an effect dependent uponfunctioning beta cells in the pancreatic islets. They bind tosulfonylurea receptors on the beta cell plasma membrane, causing closureof ATP-sensitive potassium channels leading to depolarization of thecell membrane. This in turn opens voltage-gated calcium channels,allowing influx of calcium ions and subsequent secretion of insulin.

[0011] Sulfonylureas stimulate insulin secretion but cannot enhanceinsulin sensitivity, which is the primary requirement for treatinginsulin resistance that is a most common feature characterizing thepathogenesis of type II diabetes. The thiazolidinedione class ofantidiabetic agents, represented by glitazones, does not incite insulinsecretion, but improves glycemic control by improving insulinsensitivity. Glitazones are highly selective and potent agonists for theperoxisome proliferator-activated receptor-gamma (PPARγ). Activation ofPPARγ nuclear receptors regulates the transcription of insulinresponsive genes involved in the control of glucose production,transport, and utilization.

[0012] In addition, PPARγ-responsive genes also participate in theregulation of fatty acid metabolism. The antidiabetic activity ofglitazones has been demonstrated in type II diabetes in whichhyperglycemia and/or impaired glucose tolerance is a consequence ofinsulin resistance in target tissues.

[0013] The use of combinations of sulfonylureas and glitazones have beendescribed in the art. For example, U.S. Pat. Nos. 6,150,383 and6,329,404 describe the preparation and use of unit-dose combinationcompositions of glitazones with secretagogues for the treatment ofdiabetes. The use of a combination unit-dose composition containingpioglitazone and glibenclamide was also shown to be synergistic inlowering of plasma glucose over either of the compounds administeredalone to fatty male Wistar rats. In addition, U.S. Patent ApplicationPublication No. 20020147226 A1, described the two-way combination of asulfonylurea (an insulin secretagogue) and a glitazone (an insulinsensitizer).

[0014] A combination of a sulfonylurea antidiabetic agent androsiglitazone has been disclosed in U.S. Pat. No. 5,972,973 for thetreatment of NIDDM in humans, with defined ranges of the two activescomprising 3-250 mg of sulfonylurea, and 5-50 mg of rosiglitazone.Furthermore, U.S. Pat. No. 5,859,037 discloses a composition comprising3-250 mg of a sulfonylurea and 100-1000 mg of a glitazone to obtain atherapeutic effect for the treatment of diabetes.

[0015] The prior art defines an optimum therapeutic range for the oraladministration of a combination of drugs belonging to the class ofsulfonylureas and thiazolidinediones. This allows a range of dailydoses, based on increasing the number of tablets taken per day, for thetreatment of the ailment with drugs such as glipizide, having a shortelimination half-life of about 2-3 hours. However, a singleadministration of a glitazone, for example, rosiglitazone orpioglitazone, activates the insulin receptors for an extended period andmay thus be administered as a single dose without there being a need tomaintain the plasma concentration of this drug. Likewise, use of asulfonylurea that possesses a long terminal half-life eliminates theneed for multiple medications of the drug and could be administeredonce-daily at a conventional dose. Drugs such as, for example, glyburide(terminal half-life of 10 hours) and glimepiride (terminal half-life ofmore than 5 hours), are suitable examples (See Physician's DeskReference, 2002).

[0016] However, there is no availability in clinical practice of suchcombinations for the simultaneous immediate delivery of a glitazone anda sulfonylurea, all in one physically and chemically stable dosage formfor ready once-a-day administration. A need for such a dosage formexists. The availability of a dosage form that can provide therapeuticlevels of a sulfonylurea and a thiazolidinedione from the same unit-dosecomposition would be extremely constructive in clinical practice forglycemic control in the treatment of NIDDM. Such a product would improvethe treatment of NIDDM through significantly enhanced patient compliancebecause of ease of administration and a reduced frequency of dosing.There is also the possibility of a significant reduction in the doses ofthe drug substances used in combination because of the synergisticaction, resulting in a possible reduction in toxicity.

[0017] Thiazolidinediones and sulfonylureas are primarily insulinsensitizers and secretagogues, respectively, with proven efficacy inlowering glucose levels in the treatment of type II diabetes. Althoughlong-acting sulfonylureas reduce glycosylated hemoglobin A_(1c),(HbA_(1c)) levels by 0.8 to 2.0% and fasting plasma glucose (FPG)concentrations by 60 to 70 mg per dL (3.3 to 3.9 mmol per L), their useremains limited, particularly in an elderly population. Renal or hepaticinsufficiency, in geriatric patients, causes elevated drug levels andalso diminishes gluconeogenic capacity, both of which increase the riskof serious hypoglycemic reactions. Elderly, debilitated or malnourishedpatients, and those with adrenal or pituitary insufficiency, areparticularly susceptible to the hypoglycemic action of suchglucose-lowering drugs.

[0018] Furthermore, the risk of hypoglycemia may be increased withcombination therapy. However, the use of glitazones in combination withglimepiride alleviates such a risk. The main site of action ofglimepiride is the pancreatic beta cell, where the drug initiatesinsulin secretion by binding to the sulfonylurea receptor (SUR), but toa different part of the SUR than glyburide and other long-actingsulfonylureas. It provides a less marked stimulation of insulinsecretion in proportion to its effect on lowering plasma glucose, due toa potent extrapancreatic effect, mainly in adipocytes. This results infewer hypoglycemic episodes associated with glimepiride compared toglyburide and other long-acting sulfonylureas. This makes glimepiride asuitable sulfonylurea for use in the elderly where it is safe,efficacious and well tolerated, showing no significant effect on thecardiac or renal function of the patient (See Sinha et al., Annals ofLong-Term Care: Clinical Care and Aging (2001) 9(6):23).

[0019] Glimepiride, chemically known as1-[[p-[2-(3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido)ethyl]phenyl]sulfonyl]-3-(trans-4-methylcyclohexyl)urea, has beendescribed in U.S. Pat. No. 4,379,785, which is incorporated herein byreference. Glimepiride is a long-acting sulfonylurea having anelimination half-life of about 5-8 hours at steady state after oraladministration, which increases with higher dose. It lowers bloodglucose levels and reduces absolute HbA_(1c) levels by 1-2%. It has amarked insulin secretory effect, both in vitro and in vivo, increasingplasma insulin levels by as much as 50% in patients with type 2 diabetes(See Langtry et al., Drugs (1998) 55(4):563).

[0020] As aforementioned, the use of combination of thiazolidinedionesand short acting sulfonylureas is described in the U.S. Pat. Nos.5,972,973 and 5,859,037, but a sulfonylurea having long terminalhalf-life, particularly glimepiride, in combination with an appropriatethiazolidinedione is unknown previously in the art.

[0021] It would be desirable to provide a combination therapy ofglimepiride and a glitazone having a synergistic effect on glucosecontrol. Both of these agents act by different but complementarymechanisms. It would be desirable to add a thiazolidinedione agent toconcurrent glimepiride treatment and provide a balance of stimulatedrelease of insulin, while ameliorating insulin resistance. It would beadvantageous to provide such a combination and provide a level ofglycemic control unattainable by either medication alone.

[0022] Although the use of a combination of a thiazolidinedione and asulfonylurea has been described in the art, the art does not describethe mode of preparation of compositions of such a combination that canbe used for the therapeutic advantage to the benefit of the patient andclinician. Specifically, the use of a unit-dose composition comprising aglitazone (such as rosiglitazone or pioglitazone) and a sulfonylurea(such as glimepiride), which is also physically and chemically stableand releases both the antidiabetic agents simultaneously at a ratesimilar to that compared to the individually marketed products, such asfor example, glimepiride from Amaryl™ (Aventis) and pioglitazone fromG-Tase™ (Unichem) or rosiglitazone from Avandia™ (Smith Kline Beecham),has not been described.

[0023] Combinations of biologically active agents are especiallydifficult to formulate because of the inherent differences inphysicochemical properties, the possible drug-drug interactions betweenthe drugs, and the ingredients used for formulation of the combinationcomposition. Furthermore, the oral combination products should beadaptable so that the extent of release, the release rates and profilesfrom the combination product are comparable to the two drugs dosedconcurrently from separate formulations. This is a particularlychallenging task for the pharmaceutical formulation scientist,especially in the development of a combination product because of issuessuch as the uniformity of content of the low dose drugs in the matrix,solubility characteristics and the amounts of excipients that can beused to formulate such a dosage form.

[0024] Therefore, a need exists in the art for a chemically andphysically stable dosage form which can be administered once-a-day andwhich can provide therapeutic levels of glimepiride and athiazolidinedione, for example, pioglitazone or rosiglitazone, from thesame unit-dose composition in a pattern similar to each of the separateproducts available commercially. Such a dosage form would be extremelybeneficial in clinical practice for glycemic control in the treatment ofNIDDM for patients poorly controlled on either glimepiride or anythiazolidinedione alone.

[0025] There is also a need in the art for such a dosage form resultingin a bioequivalent product, which would provide similar in vivo releaseprofiles for the two drugs when compared with each of the marketedproducts administered individually.

[0026] There is a further need in the art for such a once-a-daycombination composition having a lower incidence of between-mealhypoglycemic events when compared with other once-a-day combinations,thus resulting in enhanced patient compliance. Also, such a once-a-daycombination composition would provide enhanced efficacy through anincrease in basal insulin levels because of the prolonged action ofglimepiride, which would be further enhanced by the insulinsensitization provided by a thiazolidinedione.

SUMMARY OF THE INVENTION

[0027] It is therefore an object of the present invention to provide achemically and physically stable pharmaceutical composition for oraladministration comprising a combination of pharmaceutically effectiveamounts of glimepiride and a thiazolidinedione.

[0028] It is a further object of the present invention to provide apharmaceutical composition that provides an immediate release ofglimepiride and a thiazolidinedione, simultaneously.

[0029] It is also an object of the present invention to provide apharmaceutical composition that provides simultaneous release ofglimepiride and a thiazolidinedione at rates substantially similar tothose obtained with separate administration of an immediate releasecomposition of glimepiride and an immediate release composition of athiazolidinedione.

[0030] It is another object of the present invention to provide apharmaceutical composition for a combination of glimepiride and athiazolidinedione wherein the glimepiride has a mean particle size ofless than about 30 microns and a particle size distribution such that atleast 90% of the particles are less than about 75 microns.

[0031] It is yet another object of the present invention to provide amethod of use of this combination for the treatment of diabetes and itsassociated maladies.

[0032] In keeping with these objectives, the present invention relatesto a pharmaceutical composition for a combination of glimepiride and athiazolidinedione or a pharmaceutically acceptable salt thereof whereinthe composition provides a simultaneous release of each drug at ratessubstantially similar to those obtained with separate administration ofimmediate release dosage forms of glimepiride and a thiazolidinedione.

[0033] Glitazones, such as for example, pioglitazone and rosiglitazone,have low solubility characteristics. Rosiglitazone is readily soluble ina buffered aqueous solution with a pH of 2.3. Its solubility decreaseswith increasing pH in the physiological range (See Physician's DeskReference, 2002). However, glimepiride is practically insoluble in water(100 μg/ml or less at 25° C.) and also hydrophobic in nature. Thebioavailability of such a drug depends on its rate of solution uponadministration. The hydrophobicity of this drug poses the keyformulation impediment as it results in poor dissolution. A quickdisintegration of the combination product provides dissolution rates ofglimepiride unsuitably low due to the inherent solubility properties ofthe drug substance itself. It has now been found through extensivein-vitro testing that the reduced dissolution rates and thusbioavailability are related to the particle size and the particle sizedistribution of the glimepiride. The micronization of glimepirideimproves the dissolution characteristics of the drug from thecombination product and thus improves the bioavailability. However, ithas been found that particles that were too small resulted in highdissolution rates of glimepiride and hence, higher blood levels withconsequent risk of hypoglycaemia. Larger particles, however, do notdissolve sufficiently rapidly to give comparable dissolution profileswith the commercially available separate products.

[0034] It is therefore necessary to have a closely defined particle sizedistribution of the glimepiride in the combination product with athiazolidinedione, such as a glitazone. The selection of a specificparticle size fraction of glimepiride enables the production of acombination product exhibiting a glimepiride dissolution profilecomparable to that obtained with the individual co-administration of aglitazone and glimepiride, and thus ensures the required equivalentbioavailability.

[0035] The usual starting dose of glimepiride at initiation of therapyis 1 to 2 mg followed by a maintenance dose of 1 to 4 mg once daily.Being a low dose drug, another challenge in formulating the dosage formof glimepiride as a combination product is to ensure homogeneity andthus good drug content uniformity. Furthermore, glimepiride isinherently very potent and thus the correct dose needs to beadministered to the patient. It is extremely important during theformulation of solid oral dosage forms to avoid segregation of thepowder blend and to maintain content uniformity of such low dose drugs.Uniformity of drug content is a serious limitation, and if not strictlyassured, there could be a possibility of the desired therapeutic effectnot being achieved through an underdose. On the other hand, incidents ofhypoglycemia may occur due to overdose.

[0036] To achieve content uniformity of low dose drugs, methods, such asfor example, the solution method or powder dilution method, areconventionally used for formulating the dosage forms. For the former, asolution of a drug dissolved in a proper solvent is uniformly dispersedin the excipient and then this dispersion is used for further processingto provide the dosage form. For the latter, geometric mixing is adopted,wherein the drug is first compounded with a small portion of theexcipient followed by mixing with a slightly larger portion of theexcipient and so on, until the desired mix is obtained which is thenfurther processed to provide the dosage form.

[0037] However, the solution method is not suitable for hydrophobicdrugs, such as for example, glimepiride, due to their low aqueoussolubility. A drug in solid form when in contact with a solvent maychange its crystal form, for example, a hydrate may change into asolvate and thus change the effective moiety. Furthermore, when thesolution containing the drug is dispersed with the excipients for thepreparation of the desired dosage form, the removal of solvent resultsin precipitation of the drug. The particle size of the drug may changeand may affect the stability of the drug. This may result in the changein its physico-chemical characteristics and thus its biopharmaceuticalbehavior.

[0038] In addition, it is difficult to produce drug preparations havingexcellent drug content uniformity using the powder dilution methodespecially when a potent, low dose drug substance is involved. Inparticular, uniform mixing of aggregates of the drug with excipients isnot attained by simple mixing and thus a homogenizing step such asmixture pulverization is required. Hence, for obtaining uniformity ofdrug content, complex manufacturing procedures are required.

[0039] It has now been found that the need for complex manufacturingprocedures for attaining content uniformity can be avoided usingmicronized glimepiride with commercially available excipients,particularly lactose. Without wishing to be bound by any particulartheory, it is postulated that one explanation for the achievement ofcontent uniformity is that micronization of glimepiride develops asurface charge on the fine drug particles, which when blended withexcipient particles of large size, adhere electrostatically to thelarger excipient particles thus aiding in the prevention of segregationof the powder blend. This high binding affinity and low demixingpotential of the micronized glimepiride helps in attaining enhancedhomogeneity resulting in good content uniformity.

[0040] Thus, in one embodiment of the present invention, apharmaceutical composition for oral administration comprises acombination of a pharmaceutically effective amount of glimepiride and apharmaceutically effective amount of a thiazolidinedione or apharmaceutically acceptable salt thereof, wherein the glimepiride has amean particle size of less than about 30 microns and a particle sizedistribution such that at least 90% of the particles are less than about75 microns. A further embodiment of the present invention comprises thissame pharmaceutical composition wherein the composition provides asimultaneous release of each drug at rates substantially similar tothose obtained with separate administration of immediate release dosageforms of glimepiride and a thiazolidinedione.

[0041] The present invention also includes antidiabetic combinationcompositions, and processes for the preparation of such compositions,comprising combinations of glimepiride and a thiazolidinedione for thetreatment of NIDDM for improving glycemic control.

[0042] In one embodiment of the invention, a composition comprisingglimepiride and a thiazolidinedione, all in the same dosage form, can beprepared in the form of, for example, pellets, beads, granules, tabletsor capsules.

[0043] Another embodiment of the present invention includes apharmaceutical composition in the form of a bilayered dosage form in aunit-dose combination for the simultaneous delivery of glimepiride and athiazolidinedione to provide a synergistic effect for the treatment ofdiabetes. The term “bilayered” as used herein is meant to encompasssolid dosage forms such as tablet formulations where there are twoseparate drug layers, one on top of the other with only one surface inmutual contact. These may be prepared by compressing additionalgranulation on a previously compressed granulation, or alternatively byfeeding previously compressed tablets into a machine and compressinganother granulation layer around the preformed tablets. The term“bilayered” also includes formulations where one drug component iscoated onto the second drug component, which may be in the form of, forexample, tablets, capsules, granules, pellets or beads.

BRIEF DESCRIPTION OF THE DRAWINGS

[0044]FIG. 1 shows the comparative dissolution profile of pioglitazoneHCl from G-Tase™ (Unichem) 15 mg tablets, and from an embodiment of theunit-dose combination composition of the present invention comprisingglimepiride 1 mg+pioglitazone HCl 15 mg tablets (Example 1).

[0045]FIG. 2 shows the comparative dissolution profile of glimepiridefrom Amaryl™ (Aventis) 1 mg tablets, and from an embodiment of theunit-dose combination composition of the present invention comprisingglimepiride 1 mg+pioglitazone HCl 15 mg tablets (Example 1).

[0046]FIG. 3 shows the comparative dissolution profile of pioglitazoneHCl from G-Tase™ (Unichem) 15 mg tablets, and from an embodiment of theunit-dose combination composition of the present invention comprisingglimepiride 2 mg+pioglitazone HCl 15 mg tablets (Example 2).

[0047]FIG. 4 shows the comparative dissolution profile of glimepiridefrom Amaryl™ (Aventis) 2 mg tablets, and from an embodiment of theunit-dose combination composition of the present invention comprisingglimepiride 2 mg+pioglitazone HCl 15 mg tablets (Example 2).

[0048]FIG. 5 shows the comparative dissolution profile of pioglitazoneHCl from G-Tase™ (Unichem) 30 mg tablets, and from an embodiment of theunit-dose combination composition of the present invention comprisingglimepiride 1 mg+pioglitazone HCl 30 mg tablets (Example 3).

[0049]FIG. 6 shows the comparative dissolution profile of glimepiridefrom Amaryl™ (Aventis) 1 mg tablets, and from an embodiment of theunit-dose combination composition of the present invention comprisingglimepiride 1 mg+pioglitazone HCl 30 mg tablets (Example 3).

[0050]FIG. 7 shows the comparative dissolution profile of pioglitazoneHCl from G-Tase™ (Unichem) 30 mg tablets, and from an embodiment of theunit-dose combination composition of the present invention comprisingglimepiride 2 mg+pioglitazone HCl 30 mg tablets (Example 4).

[0051]FIG. 8 shows the comparative dissolution profile of glimepiridefrom Amaryl™ (Aventis) 2 mg tablets, and from an embodiment of theunit-dose combination composition of the present invention comprisingglimepiride 2 mg+pioglitazone HCl 30 mg tablets (Example 4).

DETAILED DESCRIPTION

[0052] An embodiment of the present invention includes an immediaterelease unit-dose composition for the once-a-day administration ofglimepiride, along with a thiazolidinedione, such as for example,pioglitazone or rosiglitazone, which is physically and chemicallystable, and releases each drug from the unit-dose composition at a ratesimilar to that of the individually marketed products such as, forexample, glimepiride from Amaryl™ (Aventis), and pioglitazone fromG-Tase™ (Unichem) or rosiglitazone from Avandia™ (Smith Kline Beecham).Another embodiment of the present invention further includes processesfor the preparation of such compositions and their use for the controlof hyperglycemia in the treatment of NIDDM and associated conditions.

[0053] In accordance with the invention, any salts, solvates, hydrates,polymorphs, complexes and such other products of glimepiride, may alsobe employed.

[0054] According to an embodiment of the invention, the particle size ofthe glimepiride is such that the mean particle size is less than about30 microns, and the particle size distribution is such that at least 90%of the glimepiride particles are less than about 75 microns.

[0055] Preferably, the particle size of the glimepiride is such that themean particle size is about 25 microns, and the particle sizedistribution is such that at least 90% of the glimepiride particles areless than about 60 microns.

[0056] According to another embodiment, the micronized glimepiride isevenly distributed over different sized sieve fractions ofthiazolidinedione and other excipients resulting in a homogenousmixture. Furthermore, during processing constituent segregation isminimized resulting in a powder blend with good content uniformity.

[0057] The glimepiride of the invention is preferably present in anamount of from about 0.2% to about 8% by weight, more preferably fromabout 0.5% to about 3.5% by weight of the total composition.

[0058] The thiazolidinediones that could be used in accordance with theunit-dose combinations of the present invention include, but are notlimited to, pioglitazone and rosiglitazone, and other medicinally activeand pharmaceutically acceptable forms from the glitazone class ofcompounds, including their salts, solvates, hydrates, polymorphs,complexes and such other products.

[0059] Preferably, the pharmaceutical composition of the inventionincludes each drug, glimepiride and the thiazolidinedione, in an amountthat is typically administered for a given period of time. This amountincludes a pharmaceutically effective amount of the drug, which is anamount large enough to significantly positively modify the condition tobe treated, but small enough to avoid serious side-effects (at areasonable benefit/risk ratio), within the scope of sound medicaljudgement.

[0060] The thiazolidinedione of the invention is preferably present inan amount of from about 0.5% to about 45% by weight of the totalcomposition.

[0061] In those embodiments of the invention where the thiazolidinedioneis pioglitazone or a pharmaceutically acceptable salt of pioglitazone,it is preferably present in an amount of from about 4% to about 45% byweight, more preferably from about 12% to about 38% by weight, of thetotal composition.

[0062] In embodiments of the present invention where thethiazolidinedione is rosiglitazone or a pharmaceutically acceptable saltof rosiglitazone, it is preferably present in an amount of from about0.5% to about 10% by weight, more preferably from about 1.5% to about 7%by weight, of the total composition.

[0063] According to an embodiment of the present invention, thepharmaceutical composition may also contain other conventionalpharmaceutically acceptable excipients known in the art of formulationdevelopment. The present invention is not to be construed as beinglimited to any particular excipient or class of pharmaceuticalexcipients. In addition, any adjuvants employed are preferably selectedsuch that there is no interaction that would substantially reduce thepharmaceutical efficacy of the composition of the present invention.Pharmaceutical excipients used are preferably of high purity and lowtoxicity to render them suitable for administration. The choice of theseexcipients and the amounts to be used is considered to be within thepurview of one of ordinary skill in the art and would depend on the typeof individual dosage form. Such excipients include, but are not limitedto, binding agents, diluents, disintegrants, glidants, wetting agents,lubricating agents, pigments, dyes and the like, and are known topersons skilled in the art of developing and manufacturingpharmaceutical solid oral dosage forms.

[0064] Examples of the binding agents which may be used in the presentinvention include, but are not limited to, hydroxypropyl cellulose,hydroxyethyl cellulose, sodium carboxymethyl cellulose,polyvinylpyrrolidone, alginates, starches, polysaccharides, and/ormixtures thereof. When present, the binder agent preferably comprisesabout 1% to about 10% by weight of the total composition.

[0065] According to another embodiment of the present invention, thepharmaceutical composition may also contain one or more of awater-soluble and/or a water dispersible diluent. Examples of watersoluble diluents that may be used in the present invention include, butare not limited to, lactose, calcium sulphate, calcium phosphates,mannitol, dextrates, dextrin, dextrose, sucrose and the like. Waterdispersible diluents, which refer to water insoluble pharmaceuticalexcipients that disperse readily in water, include but are not limitedto, cellulose based excipients such as microcrystalline cellulose,powdered cellulose, starches such as corn starch, pregelatinized starch,clays or clay minerals such as kaolin, bentonite, attapulgite, and thelike. When present, the diluent preferably comprises about 15% to about85% by weight of the total composition.

[0066] Suitable disintegrating agents that may be used in the presentinvention include but are not limited to starch, croscarmellose sodium,sodium starch glycolate, crospovidone, cross-linked carboxymethylstarch, magnesium aluminium silicate, polyacrylin potassium, and thelike. When present, the disintegrating agent is preferably present in anamount of from about 1% to about 10% by weight of the total composition.

[0067] In accordance with the present invention, other additives, suchas for example, surface active agents, bioavailability modifiers,modifiers for absorption and the like, may also be present in thecomposition, and when present, they preferably comprise about 0.5% toabout 5% by weight of the total composition. According to a furtherembodiment of the invention, the composition may optionally include abuffering agent, complexing agent and the like.

[0068] According to the present invention, the pharmaceuticalcomposition may be prepared in a variety of forms including, but notlimited to, pellets, beads, granules, tablets or capsules.

[0069] In those embodiments of the present invention wherein thepharmaceutical composition is in the form of a solid dosage form, it maycontain in addition to the above ingredients, pharmaceutical-grademagnesium stearate or stearic acid and the like as a glidant, talc andthe like as an anti-adherent, silicon dioxide or hydrogenated vegetableoil and the like as a lubricant, and ferric oxide and the like as acoloring agent.

[0070] According to an embodiment of the present invention, thepharmaceutical composition may be optionally coated with a rapidlydissolving water-soluble film coat. The examples of water-solublepolymers include, but are not limited to, hydroxypropyl methylcellulose,hydroxypropyl cellulose, and the like. When such an optional coat ispresent, the solid unit dosage form in accordance with the presentinvention is preferably coated to a weight build-up of about 1% to about10% by weight, more preferably from about 1% to about 4% by weight ofthe total composition.

[0071] In those embodiments of the present invention wherein thepharmaceutical composition is in the form of a capsule dosage form, thecapsule shell may be, for example, of a hard gelatin or a soft gelatintype.

[0072] In accordance with an embodiment of the present invention,glimepiride is subjected to micronization using any milling apparatuswhereby it is reduced to a very fine powder due to attrition of theparticles by collisions between particles and between particles andmachine surfaces. The micronization may be advantageously carried out inan accelerated air-jet mill wherein collision of drug particles witheach other under a high pressure stream of air causes reduction ofparticle size and increases the specific surface area of the material,manifold. The period of milling may vary depending on the size of themill, the velocity of the air, the type of feed material and thequantity of feed material. The effects of these variables are well knownin the art, and the present invention may be processed over a range ofthese variables. However, the comminution operation is preferablycarried out until the powder obtained is such that the mean particlesize is less than 30 microns and the particle size distribution is suchthat at least 90% of the particles are less than about 75 microns.

[0073] In an embodiment of the method of the present invention, thepharmaceutical composition is prepared by blending drugs, such asglimepiride and a thiazolidinedione, with pharmaceutically acceptableexcipients, such as inert diluents and the like. The blend is directlycompressed into tablets or may be filled into capsules. In anotherembodiment for the process of preparing the composition of the presentinvention, the drugs are blended with excipients, and the blend is rollcompacted and then sized to obtain granules. The granules may be filledinto capsules or compressed into tablets. In yet another embodiment forthe process of preparing the composition of the present invention, thedrugs are blended with above-mentioned excipients, and the blend isgranulated with a solution of a binder. The granules so obtained aredried, sized and may be filled into capsules or compressed into tablets.

[0074] In those embodiments of the present invention wherein theforegoing composition is, for example, a tablet dosage form, theglimepiride and the rosiglitazone or pioglitazone may be intimatelydispersed in the same tablet matrix or a bilayered tablet may beprepared which encompass formulations where two separate layers areprepared by the compression of individual granules containing the twoactive agents, or one active agent is present in a coating which isformed on a core containing the second active agent.

[0075] In those embodiments of the present invention wherein theforegoing composition is, for example, a capsule dosage form, it maycontain a simple blend of the two active agents with the addition ofsuitable excipients or non-pareil sugar seeds and the like coated withthe active ingredients filled into the capsule shells. Of course, theuse of a tablet of one active and a powder or granules of the otheractive, both filled into a capsule is well within the spirit or scope ofthis invention as well.

[0076] In those embodiments of the present invention wherein theforegoing composition is in the form of spherical pellets or beads, suchdosage forms may be produced by known techniques of extrusion andspheronisation techniques or techniques based on high shear granulationor fludized bed techniques, for example. Furthermore, embodiments of theinvention including single unit pellets can be produced on an industrialscale using lozenge and troches cutting machines.

[0077] According to an embodiment of the invention, the combinationunit-dose compositions could contain, for example, from about 0.5 toabout 10 mg of glimepiride, and from about 5 to about 50 mg ofpioglitazone or about 0.5 to about 10 mg of rosiglitazone. Preferably,these combination unit-dose compositions could contain from about 1 toabout 4 mg of glimepiride, and from about 15 to about 45 mg ofpioglitazone or about 2 to about 8 mg of rosiglitazone.

[0078] As would be understood by one of ordinary skill in the art, forany particular subject being treated, e.g., a mammal, specific dosageregimens should be adjusted according to the individual need, and suchindividual dosage regimens are within the scope of the invention. It isfurther to be understood that the dosages set forth herein are examplesonly and they do not to any extent limit the scope of the practice ofthe present invention. Preferably, the compositions of the invention areadministered to the patients in need thereof either immediately beforeor after a meal in the morning or at night. That is, the preferred timesfor administering the compositions of the present invention are anytimewithin approximately 5-60 minutes before or after a meal in the morning,such as breakfast, or an evening meal, such as dinner.

[0079] The following examples further illustrate this invention and arenot to be construed as limiting the scope of the invention. The examplesare illustrative only and are to be read in conjunction with thedescription above to provide a further understanding of the presentinvention, and an exemplary outline of the process for preparing thecomposition of the invention.

EXAMPLE 1

[0080] This example illustrates the present invention in the form ofunit-dose tablet containing glimepiride and pioglitazone as the activeingredients. The pharmaceutical composition of this example is givenbelow in Table 1. TABLE 1 Weight of the Ingredients composition (mg)Pioglitazone hydrochloride 16.6 (equivalent to pioglitazone 15 mg)Glimepiride 1.0 Microcrystalline cellulose 15.0 Lactose monohydrate 76.9Polyvinylpyrrolidone (K-30) 3.5 Crosslinked 5.0 polyvinylpyrrolidonePurified talc 0.5 Magnesium stearate 1.0 Colloidal silicon dioxide 0.5Coating Compostion: Weight of the coating Ingredients composition (mg)Hydroxypropyl 2.0 methylcellulose Polyethyleneglycol 400 0.3 Titaniumdioxide 0.5 Coloring agent (FD&C Blue 0.5 No. 1) Isopropyl alcohol q.s.Methylene chloride q.s.

[0081] In this example micronized glimepiride (particle size of about 25μ) was mixed with a part of lactose monohydrate in geometric proportion.Pioglitazone hydrochloride was added to the above blend and mixed well.Microcrystalline cellulose and remaining part of lactose monohydratewere further added to the above mixture and granulated with a dispersionof polyvinylpyrrolidone in isopropyl alcohol. The dried granules weresifted through a 850 μm mesh (British Standard Sieve (BSS) No. 18). Thesized granules were blended with crosslinked polyvinylpyrrolidone,magnesium stearate, talc and colloidal silicon dioxide prior tocompression into tablets.

[0082] Hydroxypropyl methylcellulose and polyethylene glycol weredissolved in a mixture of methylene chloride and isopropyl alcohol.Titanium dioxide was then dispersed in the above solution andhomogenized. The tablets were film coated with this coating solution toa desired weight gain.

[0083] Characterization Studies

[0084] Content Uniformity of the Novel Unit-Dose CombinationComposition:

[0085] The coated tablets prepared above according to example 1 weretested for the uniformity of content of pioglitazone and glimepiride.Ten (10) sample tablets (denoted below in Table 2 as CU-1 through CU-10)demonstrated an assay of glimepiride of 101.21% of label claim (1 mg pertablet) with a uniformity of content of 101.04%±5.48% and an assay ofpioglitazone of 100.16% of label claim (15 mg per tablet) with auniformity of content of 101.88%±5.43%. The content uniformity of eachtablet studied in this example is given below in Table 2. TABLE 2Tablets for Content Glimepiride Pioglitazone Uniformity 1 mg (%) 15 mg(%) CU-1 97.44 93.07 CU-2 98.00 98.54 CU-3 98.45 96.28 CU-4 100.00 98.23CU-5 97.91 100.38 CU-6 108.67 107.50 CU-7 108.75 108.32 CU-8 93.76100.98 CU-9 108.49 107.26 CU-10 98.96 108.23  Mean = 101.04  Mean =101.88  SD = 5.48  SD = 5.43 RSD = 5.42 RSD = 5.42

[0086] The data demonstrates good uniformity of content of theglimepiride and pioglitazone hydrochloride in the tablets.

[0087] Dissolution Profile of the Novel Unit-Dose CombinationComposition:

[0088] The dissolution profile of the unit-dose combination compositionas prepared above according to example 1, was compared to the profilesof each of the individually marketed products contained therein.

[0089] The dissolution profile for pioglitazone from the unit-dosecombination composition of example 1 above was compared to that obtainedfor pioglitazone (15 mg) from its individually marketed form (G-TASE™(UNICHEM)). The dissolution results are recorded in Table 3 and theprofiles are given in FIG. 1. As shown in FIG. 1, which plots the datafrom Table 3, the unit-dose combination composition of example 1releases the pioglitazone at a substantially similar rate to that of theindividually marketed product. TABLE 3 Cumulative percent pioglitazonereleased Glimepiride 1 mg + Time G-Tase ™ 15 mg pioglitazone 15 mgtablets (Minutes) (Unichem) (Example 1) 5 85.60 80.87 10 98.91 98.00 15100.32 100.00 30 101.11 100.00 45 101.23 100.08 60 101.23 100.23

[0090] Furthermore, the dissolution profile for glimepiride from theunit-dose combination composition of Example 1 was compared to that ofglimepiride from its individually marketed form (AMARYL™ (AVENTIS)). Thedissolution results are recorded in Table 4 and the profiles are givenin FIG. 2. As shown in FIG. 2, which plots the data from Table 4, theunit-dose combination composition of Example 1 releases the glimepirideat substantially the same rate as the individually marketed product.TABLE 4 Cumulative percent glimepiride released Glimepiride 1 mg + TimeAmaryl ™ 1 mg pioglitazone 15 mg tablets (Minutes) (Aventis) (Example 1)5 78.80 79.52 10 80.22 80.63 15 81.43 82.55 30 84.52 83.42 45 85.6885.18 60 88.33 87.72

[0091] Stability of the Novel Unit-Dose Combination Composition:

[0092] The unit-dose combination composition of Example 1, was alsosubjected to accelerated stability testing by storing the product incontrolled temperature chambers at 40° C. and 75% relative humidity forthree (3) months. There was no change in the physical properties of thetablets such as color and shape. Furthermore, there was no chemicaldegradation of the active agents as seen from the assay values at threemonths, which were 100.68% and 99.11% of the respective label claims ofpioglitazone and glimepiride.

[0093] Thus, this example 1, which employs pioglitazone hydrochlorideand glimepiride as the active agents of the composition, shows that thenovel unit-dose combination composition of the present invention isphysically and chemically stable under accelerated stability testingconditions of elevated temperature and humidity.

EXAMPLE 2

[0094] This example illustrates the present invention in the form ofunit-dose tablet containing pioglitazone (15 mg) and a higher dose ofglimepiride (2 mg) than was used in Example 1. The pharmaceuticalcomposition of this example is given below in Table 5. TABLE 5 Weight ofthe Ingredients composition (mg) Pioglitazone hydrochloride 16.6(equivalent to pioglitazone 15 mg) Glimepiride 2.00 Microcrystallinecellulose 15.0 Lactose monohydrate 76.0 Polyvinylpyrrolidone (K-30) 3.5Crosslinked 5.0 polyvinylpyrrolidone Purified talc 0.5 Magnesiumstearate 1.2 Colloidal silicon dioxide 0.5 Coating Compostion: Weight ofthe coating Ingredients composition (mg) Hydroxypropyl 2.0methylcellulose Polyethyleneglycol 400 0.3 Titanium dioxide 0.5 Coloringagent (FD&C Blue 0.5 No. 1) Isopropyl alcohol q.s. Methylene chlorideq.s.

[0095] In this example the tablets were prepared and studied for contentuniformity, dissolution and stability as described previously in example1.

[0096] Characterization Studies

[0097] Content Uniformity of the Novel Unit-Dose CombinationComposition:

[0098] The coated tablets of Example 2 were tested for the uniformity ofcontent of pioglitazone and glimepiride. Ten (10) sample tablets(denoted below in Table 6 as CU-1 through CU-10) demonstrated an assayof glimepiride of 100.22% of label claim (2 mg per tablet) with auniformity of content of 99.44%±3.73% and an assay of pioglitazone of100.63% of label claim (15 mg per tablet) with a uniformity of contentof 100.37%±3.56%. The content uniformity of each tablet studied in thisexample is given below in Table 6. TABLE 6 Tablets for ContentGlimepiride Pioglitazone Uniformity 2 mg (%) 15 mg-(%) CU-1 98.11 97.64CU-2 98.43 102.75 CU-3 97.57 97.32 CU-4 99.39 96.44 CU-5 94.67 104.67CU-6 96.37 99.87 CU-7 104.23 98.71 CU-8 98.51 106.98 CU-9 99.72 101.77CU-10 107.36 97.41 Mean = 99.44  Mean = 100.37  SD = 3.73  SD = 3.56 RSD= 3.75 RSD = 3.54

[0099] The data demonstrates good uniformity of content of pioglitazonehydrochloride and for higher dose of glimepiride in the tablets.

[0100] Dissolution Profile of the Novel Unit-Dose CombinationComposition:

[0101] The dissolution profile for pioglitazone and glimepiride from theunit-dose combination composition of Example 2 was studied as describedpreviously in example 1. The dissolution results for pioglitazone asrecorded in Table 7 and as plotted in the profiles given in FIG. 3reveal that pioglitazone is released from the unit-dose combinationcomposition of Example 2 at a substantially similar rate to that of theindividually marketed product. TABLE 7 Cumulative percent pioglitazonereleased Glimepiride 2 mg + Time G-Tase ™ 15 mg pioglitazone 15 mgtablets (Minutes) (Unichem) (Example 2) 5 85.60 81.54 10 98.91 97.91 15100.32 99.57 30 101.11 100.00 45 101.23 100.58 60 101.23 100.93

[0102] The dissolution results for glimepiride as recorded in Table 8and as plotted in the profiles given in FIG. 4 reveal the release ofglimepiride from the unit-dose combination composition of Example 2 isat substantially the same rate as the individually marketed product.TABLE 8 Cumulative percent glimepiride released Glimepiride 2 mg + TimeAmaryl ™ 2 mg pioglitazone 15 mg tablets (Minutes) (Aventis) (Example 2)5 76.79 78.25 10 79.33 80.49 15 80.62 81.28 30 82.63 83.36 45 83.7184.92 60 88.54 86.39

[0103] Stability of the Novel Unit-Dose Combination Composition:

[0104] The unit-dose combination composition of example 2, was alsosubjected to accelerated stability testing as described in example 1.The results reveal no change in the physical properties of the tabletssuch as color and shape. Further, results indicated no chemicaldegradation of the active agents as seen from the assay values at threemonths, which were 98.47% and 98.42% of the respective label claims ofpioglitazone and glimepiride.

[0105] Thus, this example 2, which employs pioglitazone hydrochlorideand higher dose of glimepiride shows that the novel unit-dosecombination composition of the composition is physically and chemicallystable under accelerated stability testing conditions of elevatedtemperature and humidity.

EXAMPLE 3

[0106] This example illustrates the present invention in the form ofunit-dose tablet containing glimepiride (1 mg) and higher dose ofpioglitazone (30 mg) than was used in Examples 1 or 2, and a loweramount of diluent was used to regulate the release profiles. Thepharmaceutical composition of this example is given below in Table 9.TABLE 9 Weight of the Ingredients composition (mg) Pioglitazonehydrochloride 33.2 (equivalent to pioglitazone 30 mg) Glimepiride 1.00Microcrystalline cellulose 15.0 Lactose monohydrate 60.0Polyvinylpyrrolidone (K-30) 3.5 Crosslinked 5.0 polyvinylpyrrolidonePurified talc 0.5 Magnesium stearate 1.2 Colloidal silicon dioxide 0.5Coating Compostion: Weight of the coating Ingredients composition (mg)Hydroxypropyl 2.0 methylcellulose Polyethylene glycol 400 0.3 Titaniumdioxide 0.5 Coloring agent (Iron 0.5 Oxide Red & Yellow) Isopropylalcohol q.s. Methylene chloride q.s.

[0107] In this example the tablets were prepared and studied for contentuniformity, dissolution and stability as described previously in example1.

[0108] Characterization Studies

[0109] Content Uniformity of the Novel Unit-Dose CombinationComposition:

[0110] The coated tablets prepared above were tested for the uniformityof content of pioglitazone and glimepiride. Ten (10) sample tablets(denoted below in Table 10 as CU-1 through CU-10) demonstrated an assayof glimepiride of 99.78% of label claim (1 mg per tablet) with auniformity of content of 100.37%±3.53% and an assay of pioglitazone of101.37% of label claim (30 mg per tablet) with a uniformity of contentof 100.28% 2.73%. The content uniformity of each tablet studied in thisexample is given below in Table 10. TABLE 10 Tablets for ContentGlimepiride Pioglitazone Uniformity 1 mg (%) 30 mg (%) CU-1 103.22100.41 CU-2 99.71 97.88 CU-3 106.28 99.18 CU-4 97.51 103.61 CU-5 98.9299.49 CU-6 102.11 97.27 CU-7 95.28 106.31 CU-8 96.63 99.67 CU-9 104.29100.28 CU-10 99.77 98.66  Mean = 100.37  Mean = 100.28  SD = 3.53  SD =2.73 RSD = 3.52 RSD = 2.72

[0111] The data demonstrates good uniformity of content of glimepirideand for higher dose of pioglitazone hydrochloride in the tablets.

[0112] Dissolution Profile of the Novel Unit-Dose CombinationComposition:

[0113] The dissolution profile for pioglitazone and glimepiride from theunit-dose combination composition of Example 3 was studied as describedpreviously in Example 1. The dissolution results for pioglitazone asrecorded in Table 11 and as plotted in the profiles given in FIG. 5reveal that pioglitazone is released from the unit-dose combinationcomposition of Example 3 at a substantially similar rate to that of theindividually marketed product. TABLE 11 Cumulative percent glimepiridereleased Glimepiride 1 mg + Time G-Tase ™ 30 mg pioglitazone 30 mgtablets (Minutes) (Unichem) (Example 3)  5 90.78 96.55 10 99.80 100.0015 100.00 100.00 30 101.20 100.00 45 101.34 100.08 60 101.41 100.23

[0114] The dissolution results for glimepiride as recorded in Table 12and as plotted in the profiles given in FIG. 6 reveal that the releaseof glimepiride from the unit-dose combination composition of Example 3is at substantially the same rate as the individually marketed product.TABLE 12 Cumulative percent glimepiride released Glimepiride 1 mg + TimeAmaryl ™ 1 mg pioglitazone 30 mg tablets (Minutes) (Aventis) (Example 3) 5 76.82 78.87 10 79.33 80.18 15 80.62 81.54 30 82.78 83.11 45 83.7184.47 60 88.29 86.19

[0115] Stability of the Novel Unit-Dose Combination Composition:

[0116] The unit-dose combination composition of Example 3 was subjectedto accelerated stability testing as described previously in example 1.The results reveal no change in the physical properties of the tabletssuch as color and shape. Further, results indicated no chemicaldegradation of the active agents as seen from the assay values at threemonths which were 99.84% and 98.04% of the respective label claims ofpioglitazone and glimepiride.

[0117] Thus, Example 3, which employs glimepiride and higher dose ofpioglitazone hydrochloride than was used in Examples 1 or 2, with loweramounts of diluent, shows that the combination composition of thisexample is physically and chemically stable under accelerated stabilitytesting conditions of elevated temperature and humidity.

EXAMPLE 4

[0118] This example illustrates the present invention in the form ofunit-dose tablet wherein higher dose of both glimepiride (2 mg) andpioglitazone (30 mg) was used. The pharmaceutical composition of thisexample is given below in Table 13. TABLE 13 Weight of the Ingredientscomposition (mg) Pioglitazone hydrochloride 33.2 (equivalent topioglitazone 30 mg) Glimepiride 2.00 Microcrystalline cellulose 15.0Lactose monohydrate 60.0 Polyvinylpyrrolidone (K-30) 3.5 Crosslinked 5.0polyvinylpyrrolidone Purified talc 0.5 Magnesium stearate 1.2 Colloidalsilicon dioxide 0.5 Coating composition: Weight of the coatingIngredients composition (mg) Hydroxypropyl 2.0 methylcellulosePolyethylene glycol 400 0.3 Titanium dioxide 0.5 Coloring agent (FD&C0.5 Yellow No. 5) Isopropyl alcohol q.s. Methylene chloride q.s.

[0119] In this example the tablets were prepared and studied for contentuniformity, dissolution and stability as described previously in example1.

[0120] Characterization Studies

[0121] Content Uniformity of the Novel Unit-Dose CombinationComposition:

[0122] The coated tablets of Example 4 were tested for the uniformity ofcontent of pioglitazone and glimepiride. Ten (10) sample tablets(denoted below in Table 14 as CU-1 through CU-10) demonstrated an assayof glimepiride of 100.32% of label claim (2 mg per tablet) with auniformity of content of 101.23%±2.94% and an assay of pioglitazone of100.68% of label claim (30 mg per tablet) with a uniformity of contentof 100.95%+3.00%. The content uniformity of each tablet studied in thisexample is given below in Table 14. TABLE 14 Tablets for ContentGlimepiride 2 mg Uniformity (%) Pioglitazone 30 mg (%) CU-1 99.27 98.51CU-2 106.82 103.52 CU-3 102.31 98.39 CU-4 98.71 100.03 CU-5 99.61 106.26CU-6 100.81 99.87 CU-7 97.49 105.22 CU-8 103.72 97.63 CU-9 99.37 101.19CU-10 104.21 98.92 Mean = 101.23 Mean = 100.95 SD = 2.94 SD = 3.03 RSD =2.91 RSD = 3.00

[0123] The data demonstrates good uniformity of content for higher dosesof glimepiride and pioglitazone hydrochloride in the tablets.

[0124] Dissolution Profile of the Novel Unit-Dose CombinationComposition:

[0125] The dissolution profile for pioglitazone and glimepiride from theunit-dose combination composition of Example 4 was studied as describedpreviously in Example 1. The dissolution results for pioglitazone asrecorded in Table 15 and as plotted in the profiles given in FIG. 7reveal that pioglitazone is released from the unit-dose combinationcomposition of Example 4 at a substantially similar rate to that of theindividually marketed product. TABLE 15 Cumulative percent piloglitazonereleased Glimepiride 2 mg + Time G-Tase ™ 30 mg pioglitazone 30 mgtablets (Minutes) (Unichem) (Example 4)  5 90.78 96.87 10 99.80 100.0415 100.00 100.09 30 101.20 100.11 45 101.34 100.18 60 101.41 100.34

[0126] The dissolution results for glimepiride as recorded in Table 16and as plotted in the profiles given in FIG. 8 reveal the release ofglimepiride from the unit-dose combination composition of Example 4 atsubstantially the same rate as the individually marketed product. TABLE16 Cumulative percent glimepiride released Glimepiride 2 mg + TimeAmaryl ™ 2 mg pioglitazone 30 mg tablets (Minutes) (Aventis) (Example 4) 5 76.79 79.14 10 79.33 81.17 15 80.62 82.14 30 82.63 83.91 45 83.7184.77 60 88.54 85.89

[0127] Stability of the Novel Unit-Dose Combination Composition:

[0128] The unit-dose combination composition of example 4 was subjectedto accelerated stability testing as described previously in Example 1.The results reveal no change in the physical properties of the tabletssuch as color and shape. Furthermore, results indicated no chemicaldegradation of the active agents as seen from the assay values at threemonths which were 99.32% and 98.83% of the respective label claims ofpioglitazone and glimepiride.

[0129] Thus, Example 4, which employs higher doses of glimepiride andpioglitazone hydrochloride shows that the novel unit-dose combinationcomposition of the present invention is physically and chemically stableunder accelerated stability testing conditions of elevated temperatureand humidity.

What is claimed is:
 1. A pharmaceutical composition for oraladministration comprising: a pharmaceutically effective amount ofglimepiride; and a pharmaceutically effective amount of athiazolidinedione or a pharmaceutically acceptable salt of thethiazolidinedione; wherein the composition provides a simultaneousrelease of the glimepiride and the thiazolidinedione or thepharmaceutically acceptable salt of the thiazolidinedione, wherein theglimepiride is released at a rate substantially similar to that obtainedwith an individual administration of an immediate-release dosage form ofthe glimepiride, and the thiazolidinedione or the pharmaceuticallyacceptable salt of the thiazolidinedione is released at a ratesubstantially similar to that obtained with an individual administrationof an immediate-release dosage form of the thiazolidinedione or thepharmaceutically acceptable salt of the thiazolidinedione.
 2. Thecomposition of claim 1, wherein the glimepiride has a mean particle sizeof less than about 30 microns and a particle size distribution such thatat least 90% of glimepiride particles are less than about 75 microns. 3.The composition of claim 1, wherein the glimepiride has a mean particlesize of less than about 25 microns and a particle size distribution suchthat at least 90% of glimepiride particles are less than about 60microns.
 4. The composition of claim 1, wherein the glimepiridecomprises about 0.2% to about 8% by weight of the composition.
 5. Thecomposition of claim 4, wherein the glimepiride comprises about 0.5% toabout 3.5% by weight of the composition.
 6. The composition of claim 1,wherein the thiazolidinedione comprises a member selected from the groupconsisting of pioglitazone and rosiglitazone.
 7. The composition ofclaim 6, wherein the thiazolidinedione comprises pioglitazone.
 8. Thecomposition of claim 1, wherein the thiazolidinedione or thepharmaceutically acceptable salt of the thiazolidinedione comprisesabout 0.5% to about 45% by weight of the composition.
 9. The compositionof claim 7, wherein the thiazolidinedione or the pharmaceuticallyacceptable salt of the thiazolidinedione comprises about 4% to about 45%by weight of the composition.
 10. The composition of claim 8, whereinthe thiazolidinedione comprises rosiglitazone, and the thiazolidinedioneor the pharmaceutically acceptable salt of the thiazolidinedionecomprises about 0.5% to about 10% by weight of the composition.
 11. Thecomposition of claim 1, further comprising: a binding agent, a diluent,a disintegrant, a glidant, a wetting agent, a lubricant, a colorant or amixture thereof.
 12. The composition of claim 1, wherein the compositionis in a physical form selected from the group consisting of a pellet, abead, a granule, a tablet and a capsule.
 13. The composition of claim12, wherein the physical form is a tablet, and the tablet includes acoating comprising a fast-dissolving film of a water-soluble polymer.14. A pharmaceutical composition for oral administration comprising: apharmaceutically effective amount of glimepiride; and a pharmaceuticallyeffective amount of a thiazolidinedione or a pharmaceutically acceptablesalt of the thiazolidinedione; wherein the glimepiride has a meanparticle size of less than about 30 microns and a particle sizedistribution such that at least 90% of glimepiride particles are lessthan about 75 microns; and wherein the composition provides asimultaneous release of the glimepiride and the thiazolidinedione or thepharmaceutically acceptable salt of the thiazolidinedione, wherein theglimepiride is released at a rate substantially similar to that obtainedwith an individual administration of an immediate-release dosage form ofthe glimepiride, and the thiazolidinedione or the pharmaceuticallyacceptable salt of the thiazolidinedione is released at a ratesubstantially similar to that obtained with an individual administrationof an immediate-release dosage form of the thiazolidinedione or thepharmaceutically acceptable salt of the thiazolidinedione.
 15. Acomposition comprising: a pharmaceutically effective amount ofglimepiride; and a pharmaceutically effective amount of athiazolidinedione or a pharmaceutically acceptable salt of thethiazolidinedione; wherein the glimepiride has a mean particle size ofless than about 30 microns and a particle size distribution such that atleast 90% of glimepiride particles are less than about 75 microns. 16.The composition of claim 15, wherein the mean particle size is less thanabout 25 microns and the particle size distribution is such that atleast 90% of glimepiride particles are less than about 60 microns. 17.The composition of claim 15, wherein the glimepiride comprises about0.2% to about 8% by weight of the composition.
 18. The composition ofclaim 15, wherein the thiazolidinedione comprises a member selected fromthe group consisting of pioglitazone and rosiglitazone.
 19. Thecomposition of claim 15, wherein the thiazolidinedione or thepharmaceutically acceptable salt of the thiazolidinedione comprisesabout 0.5% to about 45% by weight of the composition.
 20. Thecomposition of claim 15, further comprising: a binding agent, a diluent,a disintegrant, a glidant, a wetting agent, a lubricant, a colorant or amixture thereof.
 21. The composition of claim 15, wherein thecomposition is in a physical form selected from the group consisting ofa pellet, a bead, a granule, a tablet and a capsule.
 22. The compositionof claim 21, wherein the physical form is a tablet, and the tabletincludes a coating comprising a fast-dissolving film of a water-solublepolymer.
 23. A method of treating non-insulin dependent diabetesmellitus or diabetes-related disorders, comprising: administering to amammal in need thereof, a pharmaceutical composition comprising: apharmaceutically effective amount of glimepiride; and a pharmaceuticallyeffective amount of a thiazolidinedione or a pharmaceutically acceptablesalt of the thiazolidinedione; wherein the glimepiride has a meanparticle size of less than about 30 microns and a particle sizedistribution such that at least 90% of glimepiride particles are lessthan about 75 microns; and wherein the composition provides asimultaneous release of the glimepiride and the thiazolidinedione or thepharmaceutically acceptable salt of the thiazolidinedione, wherein theglimepiride is released at a rate substantially similar to that obtainedwith an individual administration of an immediate-release dosage form ofthe glimepiride, and the thiazolidinedione or the pharmaceuticallyacceptable salt of the thiazolidinedione is released at a ratesubstantially similar to that obtained with an individual administrationof an immediate-release dosage form of the thiazolidinedione or thepharmaceutically acceptable salt of the thiazolidinedione.
 24. Themethod of claim 23, wherein the mean particle size is less than about 25microns and the particle size distribution is such that at least 90% ofglimepiride particles are less than about 60 microns.
 25. The method ofclaim 23, wherein the glimepiride comprises about 0.2% to about 8% byweight of the composition.
 26. The method of claim 23, wherein thethiazolidinedione comprises a member selected from the group consistingof pioglitazone and rosiglitazone.
 27. The method of claim 23, whereinthe thiazolidinedione or the pharmaceutically acceptable salt of thethiazolidinedione comprises about 0.5% to about 45% by weight of thecomposition.
 28. The method of claim 23, wherein the pharmaceuticalcomposition further comprises a binding agent, a diluent, adisintegrant, a glidant, a wetting agent, a lubricant, a colorant or amixture thereof.
 29. The method of claim 23, wherein the composition isin a physical form selected from the group consisting of a pellet, abead, a granule, a tablet and a capsule.
 30. The method of claim 29,wherein the physical form is a tablet, and the tablet includes a coatingcomprising a fast-dissolving film of a water-soluble polymer.
 31. Aprocess for preparing a pharmaceutical composition for oraladministration, the process comprising: mixing a pharmaceuticallyeffective amount of glimepiride with a pharmaceutically effective amountof a thiazolidinedione or a pharmaceutically acceptable salt of thethiazolidinedione; wherein the composition provides a simultaneousrelease of the glimepiride and the thiazolidinedione or thepharmaceutically acceptable salt of the thiazolidinedione, wherein theglimepiride is released at a rate substantially similar to that obtainedwith an individual administration of an immediate-release dosage form ofthe glimepiride, and the thiazolidinedione or the pharmaceuticallyacceptable salt of the thiazolidinedione is released at a ratesubstantially similar to that obtained with an individual administrationof an immediate-release dosage form of the thiazolidinedione or thepharmaceutically acceptable salt of the thiazolidinedione.
 32. A processfor preparing a composition comprising: mixing a pharmaceuticallyeffective amount of glimepiride with a pharmaceutically effective amountof a thiazolidinedione or a pharmaceutically acceptable salt of thethiazolidinedione; wherein the glimepiride has a mean particle size ofless than about 30 microns and a particle size distribution such that atleast 90% of glimepiride particles are less than about 75 microns. 33.The process of claim 32, wherein the thiazolidinedione comprises amember selected from the group consisting of pioglitazone androsiglitazone.